Pyrano- and thiopyranoindole derivatives

ABSTRACT

Pyranoindole and thiopyranoindole derivatives characterized by having an amino(lower)alkyl radical attached to either or both the 1 and 9 position of a pyrano(3,4-b)indole or thiopyrano(3,4b)indole nucleus are disclosed. The amino portion of the amino(lower)alkyl radical may be further substituted with one or two lower alkyl groups or incorporated into a heterocyclic amine radical. The derivatives having the amino(lower)alkyl radical only at position 1 are further substituted at position 1 and may be optionally substituted at positions 3,4, 5, 6, 7, 8 and 9. The derivatives having the amino(lower)alkyl radical only at position 9 possess two substitutents at position 1 and may be optionally substituted at position 3, 4, 5, 6, 7, and 8. The derivatives having an amino(lower)alkyl radical at both positions 1 and 9 are further substituted at position 1 and may be optionally substituted at positions 3,4,5, 6, 7 and 8. The pyrano- and thiopyranoindole derivatives of this invention are useful antidepressant and antiulcer agents. Methods for the preparation and use of these derivatives are also disclosed.

ilnited States Patent [191 llemerson et ai.

[451 Dee.3,i974

[73] Assignee: Ayerst, McKenna and Harrison Limited, Montreal, Canada 22 Filed: Jan. 13, 1972 21 Appl. No.: 217,627

[521 1.1.5. Cl. Natl/247.1, 260/268 TR, 260/293.57. .260/293.58. 260/3269, 260/2475 R,

[51] lint. Cl C07d 87/46 [581 Field of Search. 260/247.5 R, 268 TR, 293.57, 260/293.58, 326.9, 315, 247.1

[56] References Cited UNITED sTATEs PATENTS 3.485.844 12/1969 Kaiser et a1 260/279 3,522,259 7/1970 Kaiser et al 260/268 lrinmry lituminur-G. Thomas Todd [57] ABSTRACT Pyranoindole and thiopyranoindole derivatives characterized by having an amino(lower)alkyl radical attached to either or both the l and 9' position of a pyrano[3,4-b}indole or thiopyrano[3,4-b]indole nucleus are disclosed. The amino portion of the amino(lower- )alkyl radical may be further substituted with one or two lower alkyl groups or incorporated into a heterocyclic amine radical. The derivatives having the amino(lower)alkyl radical only at position 1 are further substituted at position 1 and may be optionally substituted at positions 3,4. 5, 6, 7. 8 and 9. The derivatives having the amino(lower)alkyl radical only at position 9 possess two substitutents at position 1 and may be optionally substituted at position 3, 4, 5. 6. 7, and 8. The derivatives having an aminotlowerlalkyl radical at both positions 1 and 9 are further substituted at position 1 and may be optionally substituted at positions 3,4,5, 6, 7 and 8. The pyranoand thiopyranoindole derivatives of this invention are useful antidepressant and antiulcer agents. Methods for the preparation and use of these derivatives are also disclosed.

1 Claim, N0 Drawings PYRANO- AND THIOIPYRANOINDOLE DERIVATIVES BACKGROUND OF THE INVENTION l. Field of the Invention This invention relates to novel pyranoindole and thiopyranoindole derivatives, to processes for their preparation and to intermediates used in these processes.

More specifically, the present invention relates to novel pyranoindole and thiopyranoindole derivatives possessing valuable pharmacologic properties. For example, these derivatives exhibit useful antidepressant properties at dosages which do not elicit undesirable side effects. Furthermore the present derivatives exhibit properties useful for the treatment and prevention of ulcers. The combination of these pharmacologic properties together with a low order of toxicity render the pyranoindoles the thiopyranoindoles of the invention therapeutically useful.

2. Description of the Prior Art Only a rather limited number of reports dealing with pyrano[3,4-b]indole derivatives are available. In the few that do exist, pyranoindoles are treated more in the manner of chemical curiosities. For the most part these reports discuss the preparation of pyranoindoles. in which the pyran portion thereof exists as a lactone. For example, sec H. Plieninger, Chem. Ber., 83, 271 (1950) and S. Sakurai and T. Ito, Nippon Kagaku Zasshi, 78, 1665 (1957); [Chem Abstr., 54, 1488f (1960)]. I

The thiopyranoindoles of the prior art, for example, -(3-aminopropyl )-l ,3,4,5-tetrahydrothiopyrano[4,3- blindole, M.E. Freed, et al., J. Med. Chem., 7, 628 (1964) are distinguished from the present compounds of this invention by having a different ring structure and by lacking substituents on the thiopyran ring.

SUMMARY OF THE INVENTION The pyranindole and thiopyranoindole derivatives of this invention are characterized by having an amino(- lower)alkyl radical attached to a pyrano[3,4-b]indole or thiopyrano[3,4-b]-indole nucleus. The preferred derivatives of this invention are represented by formula I,

in which R is lower alkyl or lower cycloalkyl; R R R and R are the same or different selected from the group consisting of hydrogen and lower alkyl; R is hy drogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, nitro or halo; R is hydrogen, lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or an amino(lower) alkyl radical of formula -Alk-NR R wherein Alk is an alkylene selected from the group consisting of CR R CR R CRRCR R CRR and CR RCR RCRR CR "R wherein R", R", R, R, R, R, R and R" are hydrogen or lower alkyl and R and R are either the same or difierent selected from the group consisting of hydrogen and lower alkyl, or R and R together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consisting of l-pyrrolidinyl, piperidino, morpholino, piperazino, 4-(lower alkyl)-lpiperazinyl and 4-[ hydroxy( lower)-alkyl 1 l piperazinyl; X is oxy or thio; and Y is lower alkyl, phenyl( lower) alkyl or an amino(lower)alkyl radical of formula -Alk---NRR wherein Allk is an alkylene selected from the group consisting of CR R, CR R V DETAILED DESCRIPTION OF THE INVENTION The term lower alkyl as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl,- isopropyl, butyl, isobutyl, 2- methylpentyl and the like.

- The term lower alkenyl as used herein contemplates both straight and branched chain alkenyl radicals containing from two to six carbon atoms and includes vinyl, ally], l-propenyl, methallyl, 2ethyl-3- butenyl and the like.

The term phenyl(lower)alkyl as used herein contemplates a phenylalkyl radical in which the alkyl portion thereof contains from one to four carbon atoms and includes benzyl, phenethyl, a-methylphenethyl and the like.

The term lower cycloalkyl as used herein contemplates saturated cyclic hydrocarbon radicals containing from three to sixcarbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl and the like.

The term lower alkoxy as used herein contemplates both straight and branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, isopropoxy and the like.

The term lower alkanoyloxy" as used herein contemplates both straight and branched chain alkanoyloxy raidcals containing from two to six carbon atoms and includes acetoxy, propionyloxy, hexanoyloxy and the like.

The'term halo as used herein contemplates halogens and includes fluorine, chlorine, bromine and iodine.

The compounds of formula I are capable of forming acid addition salts with pharmaceutically acceptable acids. Such acid addition salts are included within the scope of this invention.

The acid addition salts are prepared by reacting the base form of the appropriate compound of formula I with either one to four equivalents, depending on the number of basic nitrogens in the compound, or preferably with an excess of the appropriate acid in an organic solvent, for example, ether or an ethanol-ether mixture. These salts, when administered to mammals, possess the same pharmacologic activities as the corresponding bases. For many purposes it is preferable to administer the salts rather than the base compounds. Among the acid addition salts suitable for this purpose are salts such as the sulfate, phosphate, lactate, tartrate, maleate, citrate. hydrobromide and hydrochloride. Both the base compounds and the salts have the distinct advantage of possessing a relatively low order of toxicity.

Also included in this invention are the stereochemical isomers of the compounds of formula I which result from asymmetric centers, contained therein. These isomeric forms are prepared by different methods and are purified readily by crystallization or chromatography.

Individual optical isomers, which might be separated by fractional crystallization of the diastereoisomeric salts formed thereof, for instance, with dor l-tartaric acid or D-(+)-a-bromocamphor sulfonic acid, are also included.

Antidepressant Activity The useful antidepressant activity of the compounds of formula I and their acid addition salts with pharmaceutically acceptable acids are demonstrated in standard pharmacologic tests, such as, for example, the tests described by F. Hafliger and V. Burckhart in Psychopharmacological Agents, M. Gordon, Ed., Academic Press, New York and London, 1964, pp. 75 -83.

More specifically, as noted in the latter reference the antidepressant properties of a'compound may be demonstrated by its capacity to antagonize the depressant effects ,or reserpine. Furthermore, it is well documented that reserpine in animals products a model de- When the compounds of this invention are used as antidepressants in warm-blooded mammals, e.g., rats and mice, they may be used alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For example, they may be administeredorally in solid form containing such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions of they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough, saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects and preferably at a level that is in a range of from about 0.1 mg to about mg per kilo per day, although as aforementioned variations will oc' cur. However, a dosage level that is in the range of from about 0.5 mg to about 25 mg per kilo per day is most desirably employed in order to achieve effective results.

Antiulcer Activity The compounds of formula I of this invention possess another useful pharmacologic property; that is, they are useful antiulcer agents. More particularly, the said compounds of this invention exhibit antiulcer activity in standard pharmacologic tests, for example, the test described by D. A. Brodie and L. S. Valitski, Proc. Soc. Exptl. Biol. Med, 113, 998 (1963), based on the prevention of stress-induced ulcers.

When the compounds of formula I are employed as antiulcer agents, they may be formulated and administered in the same manner as described above for their use as antidepressant agents.

Processes For the preparation of the pyranoindole and thiopyranoindole derivatives of this invention we prefer to use as starting materials the compounds of general formula II,

in which R R R, R and R are as defined in the first instance and X is hydroxy or mercapto.

The startingmaterials of formula II in which X is hydroxy are either known, for example, tryptophol, de-

scribed by H. R. Snyder and F. J. Pilgrim, J. am. Chem. Soc. 70, 3770 (1948), or they are obtained by the following process:

(III) pounds, R. c. Elderfield, Ed., Vol. 3, John Wiley and Sons, Inc., New York, 1952, pp. 8 11, to form the desired starting material (II, X OH).

The phenylhydrazines of formula 111 are either known or are prepared according to known methods. A convenient method involves the diazotization of the appropriately substituted aniline to give the corresponding diazo derivative. The latter compound is then reduced with stannous chloride or sodium sulfite to give the corresponding phenylhydrazine, see L. F. Fieser and M. Fieser, Advanced Organic Chemistry," Reinhold Publishing Corporation, New York, 1961, p. 734.

The hydroxyaldehydes of formula IV are either known, see for example, Rodds Chemistry of Carbon Compounds, S. Coffey, Ed., Vol. 1 d, 2nd, ed., Elsevier Publishing Co., Amsterdam, 1965, pp. 44 49, or they are prepared according to known methods. A convenient method involves reduction of an appropriate lactone of formula with bis-(3-methyl-2-butyl)borane, H. G. Brown and D. B. Bigley, J. Am. Chem. Soc., 83, 486 (1961), diisobutyl aluminum hydride, L. I. Zakharkkin and I. M. Knorlina, Tetrahedron Letters, 619 (1962) or sodium aluminum hydride, L. I Zakharkin et al., Tetrahedron Letters, 2087 (1963). The appropriate lactones-utilized in this condensation are either commercially available, for example, S-valerolactone, a-methyl-butyrolactone, or they are described with a variety of methods for their preparation in organic chemistry textbooks; such as the textbooks, Methoden der Organischen Chemie, Houben-Weyl, E. Muller, Ed., Vol. Vl/2, Georg Thieme Verlag, Stuttgart, 1963, pp. 561 852 or L. F. Fieser and M. Fieser, Advanced Organic Chemistry, cited above.

Alternatively, the starting materials of formula 11 in which R R and R are hydrogen and X is hydroxy are prepared by lithium aluminum hydride reduction (N. G. Gaylord, Reduction with Complex Metal Hydrides, lnterscience Publishers, Inc., New York, 1956, pp. 322 370) of compounds of formula V described by T. Y. Shen, US. Pat. No. 3,161,654, Dec. 15, 1964:

wherein R is lower alkyl and IR and R are as defined in the first instance.

in addition, convenient processes are available for the specific synthesis of certain starting materials of formula 11. For example, starting materials of formula ll in which R R R and R are hydrogen and X is hydroxy are obtained by reduction of the appropriate ethyl 3-indoleglyoxylate with lithium aluminum hydride, British Patent 778,823 and T. Nogrady and T. W. Doyle, Can. .1. Chem., 42, 485 (1964). Starting materials of formula 11 in which R and R are hydrogen, R and R are hydrogen or lower alkyl and X is bydroxy are obtained by reacting indole or an appropriately substituted indole with ethylene oxide or lower alkyl substituted ethylene oxide according to the pro cess of M. Julia et al., Bull. Soc. Chim. Fr., 2291 (1966).

The starting materials of formula II in which X is mercapto and R R R, R and R are as defined in the first instance are obtained by the following process: The appropriate compound of formula 11 (X OH) described above, is treated with phospshorus tribromide in an inert solvent, for example, ether or carbon tetrachloride, to afford the corresponding 3-(2- bromoethyl)-indole derivative. The latter compound is then converted to the desired starting material of formula 11 (X SH) by a procedure similar to that described by N. N. Suvorov and V. N. Buyanov, Khim- Farm. Zh., 1, (1967), [Chem Abstr. 67, 73474a (1967)], for converting 3-(2-bromoethyl)-indole to indole-3-ethanethiol (11; R R R", R and R H and X SH). Accordingly, the appropriate 3-(2- bromoethyl)-indole derivative is treated with sodium or potassium thiosulfate to afford the corresponding sodium or potassium B-(3-indolyl)etlhyl thiosulfate derivative, respectively, which on treatment with strong alkali for example, sodium or potassium hydroxide, is transformed into the indolyl)ethyl]dilsulfide derivative. Reduction of the latter compound with lithium aluminum hydride gives the desired compounds of formula II.

It should be noted that the preceding process may not be entirely practical for the preparation of the compounds of formula II in which X is mercapto and R is hydroxy or lower alkanoyloxy. For this reason, the preferred starting materials of formula II for the ultimate preparation of the compounds of formula I in which R is hydroxy or lower alkanoyloxy and X is thio are the corresponding compounds of formula II in which R is benzyloxy, i.e., a hydroxyl with a protecting benzyl group or other suitable protecting group, see J. F. McOmie, Advances in Organic Chemistry, Vol. 3, R. A. Raphael, et al. Ed., Interscience Publishers, New York, 1963, pp. 191 294. When the latter compounds are used as starting materials in this manner, they are first subjected to the process (II VI VII), described below. Subsequently, the benzyloxy group is removed by hydrogenation, in the presence of a catalyst, for example, 10% palladium on carbon, just prior to affording the desired corresponding compound of formula I in which R is hydroxy. The latter are converted, if desired, to the corresponding compound of formula I in which R is lower alkanoyloxy by conventional means, for example, by treatment with the appropriate lower alkanoic anhydride preferably in the presence of pyridine. Likewise, it should be noted that similar use of the starting materials of formula 11 in which X is hydroxy and R is benzyloxy to obtain the corresponding compound of formula 1 in which R is hydroxy or lower alkanoyloxy is also preferred.

The above described starting materials of formula 11 in which R, R R, R, R and X are as defined in the first instance are now subjected to a key reaction comprising the treatment of said starting materials with a compound of formula a. COOR and Alk COOR in which R is hydrogen or lower alkyl and Alk is an alkylene secorresponding bis-[w-(3-' lected from the group consisting of CR R", CRIORIICRIZR13 d CR10R11CR12R13CRl4R15 wherein R R, R R R and R are hydrogen or lower alkyl,

b. CONRR and AlkCONWR in which Alk, R

and'R are as defined above,

c. CH OCOR and Alk -CI-I OCOR in which R is hydrogen or lower alkyl and Alk is as defined above,

(I. Alk -L in which Alk is an alkylene selected from the group consisting of CR R CHR, CR R CR R CHR and CR R CR R CR R CI'IR wherein R R, R R R R and R are as defined above and L is halo,

c. Alk NR COR in which Alk and R are as defined in the first instance and R is hydrogen or lower alkyl containing from one to five carbon atoms,

f. Alk N in which Alk is as defined in the first instance, and

g. Lower alkyl and phenyl(lower)alkyl, in the presence of an acid catalyst to yield the compounds of formula VII in which R, R R, R, R R, X and Z are as defined above and R is hydrogen.

Thereafter the appropriate compound formula VII (R H) is converted to the desired pyranoindole of formula I according to the processes described hereinafter.

M In practicing the condensation (II+ VI VII) we have found it preferable to use a solvent as a reaction medium. Any solvent inert to the reaction conditions may be used. Suitable solvents include aromatic hydrocarbon, for example benzene, or toluene, ethers and cyclic ethers, for example diethyl ether, dioxan, or tetrahydrofuran, halogenated hydrocarbons, for example methylene dichloride, or carbon tetrachloride and the like. Benzene and tetrahydrofuran are especially convenient and practical for this use. A variety of suitable acid catalysts may be used for this condensation, for example, the type of catalyst used in a Friedel-Crafts reaction, i.e. p-toluenesulfonic acid, aluminum chloride, phosphorus pentoxide, boron trifluoride, zinc chloride, hydrochloric acid, perchloric acid, trifluoroacetic acid, sulfuric acid and the like. p-Toluenesulfonic acid, aluminum chloride, boron trifluoride and phosphorus pentoxide are included among the preferred acid catalysts. The amount of acid catalysts used is not especially critical and may range from 0.01 molar equivalents to 100 molar equivalents; however; however, a range of from 0.1 to molar equivalents is generally preferred. The time of the reaction may range from 10 minutes to 60 hours, with the preferred range being from one-half to 24 hours. The temperature of the reaction may range from 20C. to the boiling point of the reaction mixture. Preferred temperature ranges include 20 to C. 7

A more detailed description of the preparation of the above intermediate compounds of formula VII and a description of their subsequent conversion to pyranoindole and thiopyranoindole derivatives of formula I are disclosed below. For convenience these descriptions are catagorized into sections according to the group selected for Z for the intermediate.

a. Preparation and Conversion of Intermediates of Formula VII (Z COOR and AlkCOOR Intermediates of formula VII (Z COOR and Alk COOR in which R is hydrogen or lower alkyl and Alk is as defined in the first instance, R is hydrogen and R, R R R", R R and X are as defined in the first instance) are readily obtained by the condensation (II UI VII) by using ketoacids or ketoesters of formula in which R is as defined in the first instance and Z is COOR or Alk COOR as defined above togethe with the starting material of formula II.

Generally comparable yields of product are obtained in this process when either the ketoacid or the corresponding ketoester is used. However, in the case where it is desired to prepare an acid compound of formula VII(R H) in which Z is AlkCOOR wherein Alk is CR R and R is hydrogen (i.e., an acid intermediate of formula VII), it is preferable to first condense the appropriate B-ketoester of formula VI rather than the corresponding B-ketoacid and then hydrolyze the resulting ester product to give the desired acid compound.

Moreover, in the general practise of this invention it is often more convenient to prepare the acid compounds of formula VII(R'=I-I) by using the ketoester instead of the ketoacid in this process and then hydrolyze the resulting ester product to the desired acid, the reson being simply that the ketoesters are generally more readily available either commercially or by synthesis.

The hydrolysis of compounds of formula VII (R =H) in which Z is COOR or Alk COOR wherein Alk is as defined in the first instance and R is lower alkyl, i.e., ester intermediates of formula VII(R =H), to their corresponding acids of formula VII (R H) is readily effected by treatment with a suitable alkali, for example, potassium hydroxide or sodium carbonate, in aqueous methanol or aqueous ethanol or by treatment with lithium iodide in a suitable organic solvent, for example, collidine, see L. F. Fieser and M. Fieser, Reagents for Organic Synthesis, John Wiley and Sons, Inc., New York, 1967, pp. 615 617.

The 11-, [3-, 'yand S-ketoacids and -ketoesters of formula VI are either known, for example, ethyl pyruvate, levulinic acid, ethyl, a,a-dimethylacetoacetate, and B,B-dimethyllevulic acid, or they are prepared by known methods described in general organic chemistry textbooks. For example, a comprehensive review on the properties and preparation of such 04-, [3-, 'yand 6-ketoacids and -ketoesters may be found in Rodds Chemistry of the Carbon Compounds, cited above, Vol. Id, pp. 226 274.

Thereafter these intermediate acids and esters of formula VII (R H) are converted to compounds of formula I in which R, R, R, R", R R", R and X are as defined in the first instance and Y is AIk-NR R in which Alk is CH or Alk-CI-I wherein Alk is as defined in the first instance and R and R are as defined in the first instance. This conversion is accomplished by amidation, reduction and if desired N-alkylation of the indolic nitrogen. The order of these steps is not critical. However, we have found the following sequence of these steps to be both convenient and practical.

First, when it is desired to prepare the derivatives of the latter group of compounds of formula I in which R is H, i.e., N-alkylation of the indolic nitrogen is not desired, either the above acid intermediate or ester intermediate may be employed.

In the case where the acid intermediate of formula VII(R= H) is employed, said acid is subjected to amidation by treatment with a lower alkyl chloroformate, preferably ethyl chloroformate, in the presence of triethylamine, affording the corresponding mixed anhydride, which is converted by treatment with the appropriate amine of formula I-INR"R in which R and R are as defined in the first instance, for example, ammonia, methylamine or dimethylamine, to yield the corresponding amide of formula VII in which Z is CONR R or AIIKICONRSR9 in which Alk, R and R are as described in the first instance.

Alternatively, the latter amides are also obtained by treating the ester intermediates of formula VII (R H) with the appropriate amine according to known amidation methods, for example, see A. L. F. Beckwith in The Chemistry of Amides, J. Zalicky, Ed, Interscience Publishers, New York, 1970, pp. 96 l05.

Secondly, the amides so obtained are reduced with a suitable complex metal hydride to yield the desired pyranoindoles and thiopyranoindoles. Examples of suitable complex metal hydrides are lithium aluminum hydride, lithium aluminum hydride-aluminum chloride, aluminum hydride-aluminum chloride, diborane and sodium borochydride-aluminum chloride. Lithium aluminum hydride is preferred.

On the other hand when it is desired to prepare the compounds of formula I of the above group in which R, R R R R, R and X are as defined in the first instance, R is lower alkyl, or lower alkenyl, propargyl, phenyl(lower)alkyl or amino(lower)alkyl and Y is -Alk--N R R in which Alk is CH or AlkCI-I wherein Alk is as defined in the first instance and R and R are as defined in the first instance, the acid or ester intermediate of formula VII (R H) are first subjected to N-alkylation by treatment with a molar excess of the appropriate organic halide, namely a lower alkyl halide, lower alkenyl halide, propargyl halide, phenyl(- lower)alkyl halide or amino(lower)alkyl halide, respectively, in an inert solvent in the presence of a protonacceptor. Suitable inert solvents include tetrahydrofuran, benzene, toluene and dimethylformamide. Suitable proton acceptors include sodium hydride, alkali metal carbonate and triethylamine. Preferred conditions for effecting this N-alkylation include the use of sodium hydride as a proton acceptor and tetrahydrofuran as an inert solvent. Although the optimum temperature and reaction time will vary depending on the reactants employed, the reaction is generally performed at the boiling point of the reaction mixture for a period of 30 minutes to 48 hours.

It) The lower alkyl halides, lower alkenyl halides, propargyl halide, phenyl(lower)alkyl halides and aminoalkyl(lower)halides employed herein are either known, for example, ethyl bromide, allyl bromide and dimethylaminoethyl chloride, or they are prepared by known methods, usually by the treatment of the corresponding alcohols with a halogenating agent, for instance, thionyl chloride, see D. J. Collins and J. J. Hobbs, Aust. J. Chem, 20, 1413 (1967) and R. B. Moffett, J. Org. Chem, 14, 862 (1949).

In this manner, the corresponding N-alkylated derivatives of the above acid and ester derivatives of formula VII are obtained. Thereafter these derivatives are sub jected to the amidation and reduction steps according to the conditions described hereinabove in this section, to afford the desired compounds of formula I in which R is lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl, or amino(lower)alkyl.

Although the above sequence of steps for the conversion of the acid and ester intermediates of formula VII (R=I-I) to the above desired pyranoindoles is come nient and efficacious, a change in the order of the steps whereby the amides of formula VII( R=H) are treated with the appropriate organic halide according to the N-alkylation conditions described above, followed by reduction with a complex metal hydride, as described above, also affords the above desired compounds of formula I, in which R is lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or amino(lower)alkyl. described above, of the resulting corresponding amide derivative in which the'indolic nitrogen is alkylated also affords the above desired compounds of formula I, in which R is lower alkyl, lower alkenyl, propargyl, phenyl(lower) alkyl or amino(lower)alkyl.

Furthermore, another change in the order of the steps for preparing the latter compounds of formula I is realized by N-alkylation as described above, of the corresponding compounds of formula I in which R is hydrogen, described above. In this case when the starting material employed is a pyranoindole or thiopyranoindole of formula I in which Y is Alk- ---NR R in which Alk is CH or Alk CI-I wherein Alk is as defined in the first instance and R is hydrogen and R is hydrogen or lower alkyl, i.e., a primary or secondary amine functin is present in the molecule in addition to the indolic nitrogen, it is expedient to use only one molar equivalent of the appropriate organic halide to avoidalkylation of the primary or secondary amine if so desired.

Another aspect of the present intermediates of formula VII relates to their conversion to compounds of formula I in which R, R R R R R, R and X are as described in the first instance and Y is Alk- -NR R in which Alk is CH or AlkCI-I wherein Alk is as defined in the first instance and R is hydrogen and R is lower alkyl, i.e., secondary amines. When it is desired to prepare the lattercompounds a modification involving the protectionof the secondary amine with a benzyl group or other suitable protecting group, see J. F. McOmie, cited below is especially convenient. For example, the aforementioned acid or ester intermediate of formula VII is reacted with an amine of formula HNR R in which R is benzyl and R is lower alkyl ac-' cording to the amidation step described above. The resulting amide is N-alkylated on the indolic nitrogen, if desired, and then reduced with a complex metal hydride according to the above procedures. Thereafter the benzyl group is removed by hydrogenolysis in the presence of a catalyst, preferably 10 percent palladium on carbon, to afford the desired secondary amine compounds of formula I.

Still another modification relates to a more general reduction of the above amides of formula VII in which Z is CONR R or Alk COl lR R wherein Alk, R and R are as defined in the first instance. In other words this modification is applicable to the reduction of tertiary, secondary and primary amides, described herein, and is a preferred modification for the reduction of the latter two. In practising this modification, the aforementioned amide of formula Vll is treated with triethyloxonium fluoroborate or dimethyl sulfate, see H. Bredereck. et al., Chem. Ber., 98, 2754 (1965), in an inert solvent. for example, methylene dichloride, whereby the corresponding iminoether fluoroborate or methyl sulfate salt is obtained, respectively. Subsequent reduction of the salt thus obtained with a complex metal hydride, similar to the reduction described previously for the amides, yields the corresponding compounds of formula I. Alternatively, the above fluoroborate or methyl sulfate salt derived from a secondary or primary amide is decomposed by base treatment, for example, with 10 percent sodium hydroxide or triethylamine, to give the corresponding iminoether which is then reduced in a like manner to the desired compound of formula I.

When applying the aforementioned steps in the preparation of compounds of formula I in which R is hydroxy or lower alkanoyloxy, it is preferable to use corresponding intermediates in which R is benzyloxy followed by the appropriate transformations as noted previously to yield the desired compounds of formula I. b. Preparation and Conversion of Intermediates of Formula VII (Z=CONRR and AlkCONRR).

The intermediates of formula VII in which R is hydrogen and Z is CONR R and AlkCOl JRR wherein R, R and Alk are as defined in the first instance, described in the previous section, aree also obtained directly by utilizing the appropriate starting materials of Formula II and a-, 3-, 'yor S-ketoamides of formula Eli-Z in which R is as defined above and Z is CONR IR or Alk-CONR R in which Alk, R and R are as defined above. The ketoamides required for this condensation are either known, for example, pyruvamide or a,a-dimethylacetoacetamide, or they are prepared by known methods, for instance,-see Rodds Chemistry of the Carbon Compounds, cited above, Vol. 1d, pp. 226274.

Thereafter these amides are converted by the reduction process, described above, to the compounds of formula I in whichR, R R R R R", and X are as defined in the first instance, R is hydrogen and Y is -AlkNRR in which Alk is CH or Alk -CI-I wherein Alk is as defined in the first instance and R and R are as defined in the first instance.

c. Preparation and Conversion of Intermediates of Formula VII (Z=CH OCOR and AlkCI-I OCOR Intermediates of formula VII in which R is hydrogen and Z is CH OCOR and Alk and R are as defined in the firstinstance, are obtained when a starting material of formula II is condensed with a ketoalcohol lower elkanoic acid ester of formula R COCI-I OCOR or R COAlk CI'I OCOR in which R, Alk and R are as defined in the first instance in the presence of a suitable acid catalyst according to the conditions described above for the condensation. (II+VI VII). The ketoalcohol lower alkyl esters are either known, for example, acetonyl acetate or 5-acetoxypentan-2-one, or are prepared by known methods, for instance, see Rodds Chemistry of the Carbon Compounds, cited above, Vol. 1d, pp. 49-54.

These intermediates of formula VII may then be utilized for the preparation of compounds of formula I of this invention in the following manner. The intermediate is hydrolyzed with an aqueous alcoholic solution of a suitable alkali, for example, sodium hydroxide in aqueous methanol to afford the corresponding primaray alcohol. The primary alcohol is then oxidized to the corresponding aldehyde. Although a variety of methods are known for the oxidation of a primary alcohol to its corresponding aldehyde, see for example, Rodds Chemistry of the Carbon Compounds, cited above, Vol. 10, pp. 4-10, we have found that the method of K.E. Pfitzner and J. G. Moffat, J. Am. Chem. Soc., 87, 5670 (1965), using N,N-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence of a suitable acid, for example, trifluoroacetic acid, is both efficsious and convenient. Thereafter the aldehyde is reacted with an amine of formula I-INRR in which R and R are as defined in the first instance to give the corresponding Schiff base, which is reduced with sodium borohydride, see E. Schenker, Angew. Chem, 73, 81 (1961), to yield compounds of formula I in which R, R R R R R and X are as defined in the first instance, R is hydrogen and Y is Alkl lR R in which Alk is CH, or Alk'CH and R and R are as defined in the first instance.

Alternatively, the latter compounds of formula I are obtained by converting the above corresponding alcohol to a reactive intermediate such as the corresponding halide, mesylate or tosylate, which are then reacted with a two molar excess of an amine of formula Hl lRR in which R and R are as defined in the first instance. Preferably this reaction is performed in a suitable inert solvent, for example, tetrahydrofuran, at the boiling point of the reaction mixture for a period of 8 to 24 hours. In connection with alkylations of amines of formula I-INRR in which R is hydrogen and R is lower alkyl as disclosed herein, it is generally preferable to perform the alkylation with the corresponding N-benzyl derivative of said amine, i.e., an amine of formula HNRR in which R is benzyl and R is lower alkyl. Thereafter, when all appropriate transformation have been performed, the N-benzyl group is removed by hydrogenolysis with a catalyst, preferably 10 percent palladium on carbon, to give the desired compounds of formula I.

Thereafter, and if desired, these latter compounds of formula I are converted to their corresponding derivatives in which R lower alkyl, lower alkenyl, propargyl,

phenyl(lower)allyl or a.rnino(lower)alkyl by N- alkylation with one molar equivalent of the appropriate organic halide in the manner described for the N- alkylation in section a.

Alternatively, the above aldehyde is oxidized with a suitable oxidizing agent to yield the corresponding acid intermediates of formula VII (R =I-I) described in section a. Although a variety of suitable oxidizing agents may be used for this purpose, for example, silver oxide, alkaline permanganate, hydrogen peroxide, we prefer to use silver oxide according to the method of M. Delepine and P. Bonnet, Compt. rend, 149, 39 (1909).

Again alternatively, the above aldehyde is converted to its oxime which on reduction with a complex metal hydride yields the corresponding primary amine of formula I in which R, R R R, R R and X are as defined in the first instance, R is hydrogen and Y is -All\;-NR R in which Alk is CH or Alk -CI-I wherein Alk is as defined in the first instance and R and R are hydrogen.

If desired these latter primary amine compounds of formula I may be N-alkylated on the indolic nitrogen in the manner described above with a molar equivalent of the appropriate organic halide to give the corresponding compounds of formula I in which R is lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or Alkl IR R wherein Alk, R and R are as defined in the first instance;

In turn these latter compounds of formula I may be further N-alkylated on the nitrogen of the primary amine with the appropriate lower alkyl halide to the corresponding compounds of formula I in which Y is --Alk-NR R wherein Alk is CH or AlkCH wherein Alk is as defined in the first instance and R is hydrogen or lower alkyl and R is lower alkyl (i.e., secondary or tertiary amines with respect to Y). In this case depending on the particular derivative desired the N-alkylation is effected with one or two moles of the alkyl halide to give respectively the secondary (R =H and R =lower alkyl with respect to Y)or tertiary amine (R E -lower alkyl with respect to Y). On the other hand the N-alkylation may be effected in two steps introducing a different alkyl group each time to afford the corresponding tertiary amine in which R and R are different lower alkyls with respect to Y.

When it is desired to prepare the above tertiary amine compounds in which R or R are either or both methyl, an alternative alkylation method comprises reacting the appropriate corresponding primary or secondary amine with an aqueous mixture of a substantial excess of formaldehyde and formic acid according to the conditions of the Eschweiler-Clarke reaction, see M.L.. Moore, Organic Reactions, 5, 301 (1949), whereby N- methylation is effected.

Another N-alkylation method which is applied to the above primary and secondary amines involves acylation with a lower alkanoic anhydride or acid halide and subsequent reduction of the resulting amide.

Furthermore, the above primary amines are used to prepare compounds of formula I in which Y is Alk- ---I IRR wherein Alk is CH or AlkCI-I and R and R together with the nitrogen atom to which they are joined from a heterocyclic amine radical as defined in the first instance. When used in this mannerthe primary amines are subjected to known N-alkyation methods, for example, see method J in Moffett, cited above, with the appropriate a,w-dibromides, for example, tetramethylene dibromide, pentamethylene dibromide, bis(2-chlorethyl)ether, bis(2'chloroethyl)benzylamine followed by hydrogenation in the presence of 10 percent palladium on carbon to remove the'protecting benzyl group, a bis( 2-chloroethyl)-lower alkylamine or a bis(2-'chloroethyl)-N-[hydroxy(lower )-alkyl]amine, to give the corresponding, desired compound of formula I wherein Y is an amino(lower)alkyl in which the amino portion thereof is pyrrolidino, piperidino morpholino, piperazino, 4-(lower)alkyl-l-piperazinyl or 4-[hydroxy-(lower)alkyl]-'l -piperazinyl, respectively.

If during the above N-alkylations it is desired to protect primary or secondary amine functions that are present in the R portion of compounds of formula I, such protection may be afforded by the use of appropriate protecting groups, for example, a benzyl group;

see also, J. F. W. McOmie in Advances in Organic Chemistry, Vol. 3, R. A. Raphael, et al., Ed, Interscience Publishers, New York, 1963, pp. 191-294.

d. Preparation and Conversion of Intermediates of For mula VII (Z A1k L).

Intermediates of formula VII in which R is hydrogen and Z is Alk L wherein Alk and L are as defined in the first instance, are obtained when a starting material of formula II is condensed with a ,Bq or 8-haloketone of formula R COAlk L in which R, Alk and L are as defined in the first instance in the presence of a suitable acid catalyst according to the conditions described above for the condensation (II-l-VI VII). The haloketones are either known, for example, 4-chlorobutan- 2-one, or they are prepared by known methods, for instance, see Rodds Chemistry of Carbon Compounds," cited above, Vol. 1 c, pp. 71 and Methoden der Organischen Chemie, Houben-Weyl, E. Muller, Ed., Vol. V/ 3, Georg Thieme Verlag, Stuttgart, 1962, pp. 511-4076.

Thereafter these intermediates of formula VII are treated with a two molar excess of an amine of formula I-INRR in which R and R are as defined in the first instance to yield the compounds of formula I in which R, R R R R R and X are as described in the first instance, R is hydrogen and Y is --Alkl IR R in which Alk is Alk as defined in the first instance and R and R are as defined in the first instance. Preferred conditions for this reaction include the use of a suitable inert solvent, for example, tetrahydrofuran, temperatures ranging from 40 C. or at the boiling point of the reaction mixture and a reaction time of from 8 to 24 hours.

If desired the latter pyranoindoles and thiopyranoindoles may be N-alkylated on the indolic nitrogen with an appropriate lower alkyl halide or aminoalkyl halide according to'the method described for the N-alkylation of the pyranoindoles and thiopyranoindoles in section a. e. Preparation and Conversion of Intermediates of Formula VII (Z AIkNR COR) Intermediates of formula VII in which R is hydrogen and Z is AlkNR COR wherein Alk, R and R are as defined in the first instance are readily obtained by the condensation (II-l-VI VII) by using ketoamides of formula in which R, Alk, R and R are as defined in the first instance together with the appropriate starting material of formula II. V 1

The ketoamides used herein are either known, for example, formamidoacetone [A. T'r eibs and W. Sutter, Chem. Ber., 84, 96 (1951)] and see [R. H. Wiley and O. H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948)] or they are preparedby known procedures, for example, see Methoden der Organischen Chemie," cited above, Vol. XI/l, 1957, especially pp. 58-62, 285289 and 508-509, and F. F. Blicke, Organic Reactions, 1,

f. Preparation and Conversion of Intermediates of Formula VII (Z Alk N Intermediates of formula VII in which R is hydrogen and Z is Alk-N0 wherein Alk is as defined in the first instance, are obtained by the condensation (II-I-VI VII) when the starting materials of formula II and appropriate a-, 8-, 'y-, and 8-nitroketones of formula in which R and Alk are as defined in the first instance are employed therein in the presence of a suitable acid catalyst. In this case trifluoroacetic acid is the'preferred acid catalyst.

The nitroketones used herein are either known, for example, l-nitro-Z-propanone, N. Levy and C. W. Scaife, J. Chem. Soc., 1 100, (1946) and -nitro-2- hexanone, II. Shechter, et al., J. Amer. Chem. Soc. 74, 3664(1952) or they are prepared by known methods, for example, see Levy, and Scaife, cited above, Shechter, et a1. cited above, Rodds Chemistry of Carbon Compounds, cited above, Vol. 1c, pp. 71-72 and Methoden der Organischen Chemie, cited above, Vol.X/1, 1971, p. 203.

Thereafter, these intermediates of formula VII are reduced with a complex metal hydride, preferably lithium aluminum hydride, to afford the pyranoindoles of formula I in which R, R R R R R and X are as defined in the first instance, Y is hydrogen and Z is -AlkNR R in which Alk is defined in the first instance and R and R are hydrogen.

If desired the latter compounds may be N-alkylated according to the methods described in section 0 to give the compounds of formula I in which R, R R, R, R R, R and X are as defined in the first instance and Y is Alk-NR R in which Alk, R and R are as defined in the first instance.

g. Preparation and Conversion of Intermediates of Formula VII (Z lower alkyl or phenyl(lower)alkyl) Intermediates of formula VII (Z lower alkyl or phenyl(lower)alkyl, R is hydrogen and R, R R, R, R R and X are as defined in the first instance) are readily obtained by the condensation (II+VI VII) by using the starting materials of formula II and the ketones of formula W II-7.

in which R is as defined in the first instance and Z is lower alkyl or phenyl(lower)alkyl.

The ketones used herein are either available commercially, for example, acetone or phenylacetone, or

they are prepared by conventional methods, for example, see P. Karrer, Organic Chemistry, 2nd. ed., Elsevier Publishing Co., Inc., New York, 1946, pp. 149-l69 and V. Migrdichian, Organic Synthesis, Vol. 1, Reinhold Publishing Corp, New York, 1957, pp. 100-129.

These intermediates of formula VII are converted to the compounds of formula I in which R, R R R R R and X are as defined in the first instance, R is (Alk)NR"R in which Alk, R and R are as defined in the first instance and Y is lower alkyl or phenyl(1ower)a1kyl by N-alkylation of the indolic nitrogen with the appropriate amino(lower)alkyl halide according to the method of N-alkylation described in section a.

Finally, it is the intention to cover all changes and modifications of the embodiment of the invention herein chosen for the purpose of disclosure which are within the scope and spirit of this invention. Such .changes and modification include those variations which depend on well known interconversions of amines, amides, acids and esters or alternation of the order of the steps in the processes disclosed herein.

For example, the act of subjecting the corresponding derivative of the starting material of formula II in which the indolic nitrogen is alkylated with a lower alkyl, lower alkenyl, propargyl, phenyl(lower)a.lkyl or amino(lower)alkyl, to condensation with an appropriate compound of formula VI according to the conditions of the key reaction taught in this present disclosure to yield the corresponding intermediate compound of formula VII in which the indolic nitrogen is so alkylated would not depart from the scope of spirit of this invention.

The following examples illustrate further this invention.

EXAMPLE I l-METI-IYL-l ,3 ,4,9-TETRAI-IYDROPYRANO[ 3 ,4- b]INDOLE-l-ACETIC ACID (VII; R CH R R R R R AND R H, X O and Z CH COOH) Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of the starting material of formula II, tryptophol (10.0 g., 0.06 moles), in 200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonic acid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate (Molecular Sieves No. 4) are added. The mixture is subjected to reflux for thirty minutes, 600 mg. more of p-toluenesulfonic acid is added and refluxing continued for 2 a hours. The molecular sieves are collected and the benzene solution washed successively with 5 percent sodium bicarbonate and water, dried over sodium sulfate, and evaporated under reduced pressure to dryness affording an oil. The oil is subjectd to chromatography on silica gel. Elution with 5 percent ether in benzene yields the ester, 1-methyl-l,3 ,4,9- tetrahydropyrane-[3,4-b-1indole-l-acetic acid ethyl es ter, as an oil, y '3 1715 cm' Hydrolysis of this ester to the title compound is effected as follows: The ester is dissolved in 230 ml. of methanol. To this is added 10 g. of KOI-I in 30 ml. of H 0 and the solution is allowed to stand at room temperature overnight. The methanol is evaporated, water added and the solution washed with benzene. The aqueous phase is acidified with 6N HO, and extracted with benzene. This organic phase is washed with water, dried over sodium sulfate and evaporated to dryness to give an oil, which is crystallized from benzene containing a trace of petroleum ether to afford the title compound, m.p. 150 152C, y,,,,,,'""3 3325 and 1705 cm.

An equivalent amount of methyl acetoacetate may replace ethyl acetoacetate in the procedure of this Example. In this case, l-methyl-1,3,4,9- tetrahydropyrano[3,4-b]indoleacetic acid methyl ester, m.p. 87 90C. after recrystallization from benzenehexane, is obtained as the ester.

An equivalent amount of propyl acetoacetate may replace ethyl acetoacetate in the procedure of this Example. In this case, 1-methyl-1 ,3 ,4,9- tetrahydropyrano[3,4-blindole-l-acetic acid propyl ester is obtained as the ester.

EXAMPLE 2 R3, R4, R5, R AND R H, x o and z CH CH COOH) A mixture of the starting material of formula II, tryptophol (500 mg.), levulinic acid (580 mg.), 75 ml. of benzene, 1.7 g. of phosphorus pentoxide and about 0.5 g. of diatomaceous earth (Celite) is stirred magnetically at room temperature for minutes and then at 70C. for 1 9% hr. The reaction mixture is filtered. The filtrate is washed three times with 5N NaOI-l; the combined aqueous phase is washed twice with ether and then rendered acidic with cold 50 percent HCl. The aqueous phase is extracted with chloroform. The chloroform extract is dried (Na SO and evaporated to dryness. The residue is crystallized from ethyl acetatepetroleum ether to afford the title compound, m.p. 104 110C, nmr (CDCI 81.47 (3H), 21.8 (4H), 2.74 (2H), 3.96 (2H), 7.18 (4H), 7.85 (1H), 9.60 (1H).

The above title compound is also obtained by following the procedure of Example 1 but replacing ethyl acetoacetate with an equivalent amount of ethyl levulinate. In this case l-methyl-1,3 ,4,9- tetrahydropyrano[3,4-b]indole-l-propionic acid ethyl ester, m.p. 116 118C., y 3 1716 cm after tained as the ester prior to hydrolysis.

EXAMPLE 3 1-METHYL-1,3,4,9- TETRAHYDROTHIOPYRANO[ 3,4-b]INDOLE- 1- ACETIC ACID (VII; R =CH R R, R, R, R AND 7 H, X S and Z CH COOl-l) lndole-3-ethanethiol 1.5 g.) and methyl acetoac etate are mixed with ml. of benzene and the solution heated for 30 min. (bath temperature C.). p-Toluenesulfonic acid (0.15 g.) is added and the reaction mixture is subjected to reflux and stirring for 12 hours. Water formed in the reaction mixture during this period is collected by a water separator. After cooling the benzene solution is washed with 10% solution of sodium bicarbonate, water, saturated brine and dried over sodium sulfate. Evaporation of the benzene solution yields the ester, l-methyl-l ,3 ,4,9- tetrahydrothiopyrano[ 3,4-blindole- 1 -acetic acid methyl ester as a semi-solid, y 3 1715 cm" This ester is then treated with aqueous alcoholic KOH in the manner described for the esters in Example 1 and 2 to afford the title compound, m.p. 147 149C., nmr (CDC1 81.86 (S, 311), 306 and 812 (611), 7.35 (multiplet, 4H), 8.71 (1H), 10.31 (111), after recrystallization from benzene-hexane.

The procedures of Examples 1, or 3 are followed to prepare other compounds of formula VII in which R, R R, R, R R and X are as defined in the first instance, R is hydrogen and Z is COOR or Alk -COOR wherein R and Alk are as defined in the first instance. Examples of such compounds of formula VII are listed in Tables I and II. In each of these examples an equivalent amount of the starting material of formula 11 listed therein is used instead of the starting material of formula 11 described in the procedures of Examples 1 and 3. Note that in each of these examples the ester obtained prior to hydrolysis is a corresponding ester compound of formula VII.

Similarly, the procedure of Example 2 is used to prepare the products listed in Tables I and II. In this case an equivalent amount of the starting material of formula II, listed therein, is used instead of the starting material of formula II described in Example 2 and an equivalent amount of the corresponding ketoacid of formula V1 is used instead of the ketoester of formula VI listed therein.

TABLE I Kelocslm' of Formula \'1 Product: [(prcllx listed l)1 lo\v)-1,3,-t.1)- O tetrnhydropyrnno- 11 [3,4-b1iudole-1- Starting umleriul of Formula 11 IUGAlk COO R (sullix listed b010\v)] l \nmplo It R R R R X R Alld-CO R lrefixl/Sullix 1 II II II II II 0 CH3 5 C 0 02115 l-methyl/marboxylic acid. CII; II II H II O C 11 C O C',II l-ethy1-3-m0thy1/l carboxylic acid. 6 11-0311; 11 II II 5-CH3 O 11-C3I'I1 C 0 CH3 1,3diisopropyI-G- mettihyll/carboxyliu act 7 C113 0113 H H 3 OH 0 CH 0 0 CH3 1,3,3-trimethyl-6- hydiloxyf/carboxylic act 8 II II II II T-CzH5 0 l1-C3H7 CO CH3 S-ethyl-Lpropyll/ carboxylic acid.

5L 11 II 0 11 I I H O C O CH; l oyclopropyl k isopropyl/learboxylic acid.

1 C111; C113 C 11 CgHs H O CO CH; l-cyclopentyligk diethyl-3,3-dimethyI// carboxylic acid.

TABLE 1 1 ---Continued Starting material of Formula II Kctoester of Formula VI 7 Product: [(pmlix listed helow)-1,3,4,U- O Tctrahydrothiopyrano- I] [3,4-h]INl)OLlC-l R -CAlk -C O O R (sullix listed hvlow)] Example R R R R R X R H H H G-OCzHs H H H S H H H C Ha II S C Ha II S G-Cl S CH3 4-CH3 S H (a) S 5-0 C CH3 CH S C2H5 n-CaH C I13 7-- O C 113 S 123 r (11 PD-C3117 S 125 CH3 CH3 EXAMPLE 126 N,N.1TRIMETHYL-l,3,4,9- TETRAHYDROPYRANO[3,4-b]-INDOLE-1- ACETAMIDE[VI1; R CH R R, R, R R AND R H, X 0 AND Z CH CON(Ci-1 To a stirred solution of 1-methyl-1,3,4,9- tetrahydropyrano[3,4-b]indole-1-acetic acid (15 g, 0.061 mole), prepared as described in Example 1, in dry tetrahydrofuran (300 ml), cooled to 5C., is added triethylamine (18.5 g, 0.183 mole), followed by ethyl chloroforrnate (16.6 g, 0.153 mole). The mixture is stirred at 5C. for 2 hr. This mixture, which now contains the mixed anhydride of the above starting material, is added dropwise to a cooled 40 percent aqueous solution of the amine, dimethylamine (225 ml). The resulting mixture is stirred at room temperature for one-ha1f hour. Most of the tetrahydrofuran is evaporated, and the residue partitioned between chloroform and water. The organic phase is washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is subjected to chromatography on silica gel. Elution with ethyl acetate in benzene, followed by crystallization of the eluate from ethyl acetate affords the title compound, mp. 149 151C., 1/ '3 3375, 1634 cm.

In the same manner but replacing the 40% aqueous CII (C2115) C11 (C9115) CO C3H5 l-eyclopropyl-afidiethyl-7-ei hoxyj/ propiouie acid.

C (CQTIQQCH CII C 0 butyric acid.

omenraomcuu'ma(o mommioo solution of dimethylaminewith an equivalent amount of ammonium hydroxide (concentrated), methylamine (30 percent aqueous solution), nhexylamine (20 percent aqueous solution), diethylamine (30 percent aqueous solution), isopropylamine (40 percent aqueous solution), ethylamine percent aqueous solution), pyrrolidine (50 percent aqueous solution), piperidine, morpholine, N-methylpiperazine,

1-methyl-l,3,4,9-tetrahydropyrano[3,4-blindole-lacetamide, m.p. 158- C, N, l -dirnethyl-1,3,4,9-tetrahydropyrano[3 ,4-b]indole-l-acetamide, m.p. 138 140C, N-hexyl- 1 -methyl-1 ,3 ,4,9-tetrahydropyrano[ 3 ,4

b]indole-l-acetamide, N,N-diethyl-1-methyl-1 ,3,4,9-tetrahydropyrano[ 3,4-

b]indole-1-acetamide, m.p. 99C., N-isopropyl- 1 -methyl-1 ,3,4,9-tetrahydropyrano[ 3 ,4-

blindole-l-acetamide, m.p. 15l 153C, N-ethyl- 1 -methyl-1 ,3,4,9-tetrahydropyrano[ 3 ,4-

b]indole-l-acetamide, m.p. 152- 153C., 1-[( l-methyl-l ,3,4,9-tetrahydropyrano[3,4-b]indo1- 1-yl)acetyl] pyrrolidine, m.p. 119- 120C, 1-[( l-methyl- 1 ,3,4,9-tetrahydropyrano[ 3,4-b]indoll-yl)acetyl]-piperidine, m.p. 14 8- 149C, l-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indoll-yl)acetyH-morpholine. m.p. 1-4l 142C, and

TABLE VI NO. 01" THE EXAMPLE IN WHICH STARTING PRODUCT: [(PREFIX LISTED BELLOW) 1,3,4,9-TETRAHYDROTH1OPYRANO- MATERIAL IS [3,4-bIINDOLE-l-(SUFFIX LISTED EXAMPLE PREPARED AMINE BELOWII PREFIX/ISUFFIX 282 96 N-methyL 1methyl-4+1-methyl//propionyl]- piperazine piperazine 283 96 N-piperazine- 1-(2-hydroxyethyl)-4-[(1-methyl//) ethanol propionyl1piperazine 284 65 pyrrolidine 1 [(1-methyll/)carbonyllpyrrolidine 285 65 morpholine 4-[(1-methyl//)carbonyl]morpholine 286 66 N-ethyl- 1-ethyl-4-[(1-ethyl-3-methyl//) piperazine carbonyl 1 piperazine 287 72 piperidine 1-[(1,4-dimethyl//)acetyl)- pipe ridine 288 73 morpholine 4-[(1-ethyl//)acetyl]morpholine 289 73 Npiperazine- 1'(3-hydroxypropyl)-4-[( l -ethyl//) propanol acetyl]piperazine 290 74 pyrrolidine 1-[( l-propyl//)acetyllpyrrolidine 291 74 morpholine 4-[(1-propy1//)acetyl]morpholine 292 75 piperdine l-[(1-isopropyl//)acetyl]piperidine 293 76 piperazine l-[(3-methyl-1-propyl//)acetyl]- piperazine 294 7 8 N ethyl 1-ethyl-4-[ a, l -dimethyl// )acetyl piperazme piperazine 295 86 pyrrolidine I l-[(6-benzyloxyl-l-methyl/l) acetyl pyrrolidine 296 87 piperidine 1-[(5-methyll-propyl//)acetyl]- piperidine 298 91 morpholine 4-[( l-cyclopropy|a,a-die1hyl 3 .3-dimethyl6-ethoxyl/ )acetyl morpholine 299 97 piperazine l-[(8-acetoxy-l-ethyl-u,3,3,4,4-

pentamethyl/l )propionyl 1 piperazine 300 100 N-piperazine- 1-(2-hydroxyethyl)-4-[(1-cyc1oethanol propyl-a,a,fi,fi,4,6-hexamethyll/) propionyl lpiperazine 301 101 pyrrolidine 1-[(1,3-dimethyl-a,nr-dipropyll/) propionyl lpyrrolidine 302 103 morpholine 4-[( 1-ethyl-B,B,4,4 tetramethyl//) propionyl Imorpholine 303 108 Nprpy1- 1-propyl-4-[( l-cyclopropyla,fi

piperazine diethyl -ethoxyl/ )propionyl piperazme 304 109 pyrrolidine l-[(1-methyl//)butyryllpyrrolidine 305 109 N-piperazine- 1-(hydroxymethyl)-4-[( l-methyl/l) methanol butyryl piperazine 306 ll 1 piperidine l-[('y,'y,-diethyl-3,3-dimethyl-lpropyl/l )butyryl ]piperidine 3 07 I 13 morpholine 4-[ 7-chloro-a,fl,fi,'y,y,4,4-

heptaethyl-1-methyl//)butyrryl] morpholine 308 120 piperazine 1-[(1-butyl-6-fluoro-a,B,y,3,3,4-

hexamethyll/)butyryllpiperazine EXAMPLE 309 late l-[(2-dimethylamino)ethyl]-1-methyl-1,3 ,4,9-

1[2-(D1METHYLAM1NO)ETHYL]-1-METHYL- 1,3,4,9-TETRAHYDROPYRANO]3,4-b1lNDOLE [1; R =CH R R R R R AND R H, X O Y CH CH N(CH A solution of N,N, 1 -trimethyl-1 ,3 ,4,9- tetrahydropyrano[3,4-b]indole-1-acetamide (5.0 g, 0.018 mole), prepared as described in Example 126, is added dropwise to a cooled, well-stirred mixture of lithium aluminum hydride (1.4- g, 0.036 mole) in 200 ml of ether. Stirring is continued for one hour at room temperature, then the mixture is heated under reflux for 2 hr.

After cooling in an ice-water bath, 6.2 ml of water is added dropwise to destroy the excess hydride. Then 100 ml more of water is added and the ether phase decanted. The aqueous phase is extracted once with benzene. The combined organic phases are washed with water, dried over sodium sulfate, and evaporated to dryness to afford 5 g of oil which crystallized on standing. The crystallized product is recrystallized from ether to afford the pure title compound, m.p. 133 135C., nmr (CDC1 )81.53 (s, 3H), 2.07 (2H), 9.74 (1H), 10.55 (6H).

The corresponding oxalic acid addition salt (oxatetrahydropyrano[3,4-b]indole oxalate, has m.p. 181 183C. after crystallization from methanol-ether.

In the same manner but replacing lithium aluminum hydride with an equivalent amount of lithium aluminum hydridealuminum chloride, aluminum hydridealuminum chloride, diborane and sodium borohydridealuminum chloride, the title compound is also obtained.

N-hexyl- 1 -methyl- 1 ,3,4,9-tetrahydropyrano[ 3 ,4-

N,N-diethyl-1-methyl-1 ,3 ,4,9-tetrahydropyrano[3,4-

dole-1 -acetamide,

b indole- 1 -acetamide,

b indole- 1 -acetamide,

N-isopropy1-1-methyl-l,3 ,4,9-tetrahydropyrano[ 3 ,4- I

b indole- 1 acetamide, N-ethyl- 1 -methyl- 1 ,3,4,9-tetrahydropyrano[ 3,4-

b]indole-1-acetamide,

' 1-methyl-1-[2-( 1-pyrrolidinyl)ethyl]-1,3,4,9-

1-( 2-aminoethyl)- l -methyl-1 ,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 80 84C., y 3 3455, 3280cm, l-methyl-1-[2-(methylamino)ethyl]-1,3,4,9-

tetrahydropyrano[3,4-b]indole, m.p. 160

163C, (m.p. of corresponding oxalic acid addition salt, 140 144C), 1'[2-(hexylamino)ethy1]-1-methyl-1,3 ,4,9-tetrahydropyrano[ 3 ,4-b indole, 1-[2-(diethylamino)ethyl]-1-methyl-1,3,4,9-

tetrahydropyran0-[ 3 ,4-b]indole, 1-1 2-( isopropylamino)ethyl 1 .-methyl-1 ,3,4,9-

tetrahydropyrano-l 3 ,4-b indole, 1-[2-(ethylamino)ethyl 1 -methyl-1 ,3,4,9-

tetrahydropyrano-[ 3 ,4-b indole,

'tetrahydropyrano-[ 3 ,4-b indole, nmr (CDCl 81.62 (3H), 2.00 (m, 4H), 4.05 (m,

36 2H), m.p. of corresponding maleic acid addition salt (maleate), 192 192C., 1-methy1-1-(2-piperidinoethyl)-1 ,3 ,4,9-tetrahydropyrano[3,4-b]-indole, m.p. 146 148C, m.p. of corresponding maleic acid addition salt, 147 149C.,

l-methyl-1-(2-morpholinoethyl)-1 ,3 ,4,9-tetrahydropyrano[3,4-b]-indole, nmr (DMSO-d 81.50 (3H), 6.07 (2H), 6.87 7.65 (m, 41-1), 10.86 (1H), m.p. of corresponding maleic acid addition salt, 192 193C, and l-methyl-l-[2-(4-methyl-lpiperazinyl)ethyl l ,3 ,4,9-tetrahydropyrano[ 3 ,4- blindole, nmr (CDCl 81.47 (31-1), 2.58 (31-1), 3.87 (t, 2H), [m.p. of corresponding maleic acid addition salt (i.e. dimaleate), 208 210C], respectively.

By following the procedure of Example 309 but using as starting material an equivalent amount of one of the amide compounds of formula V11, described in Examples 127 to 308 instead of N,Nl-trimethyl-1,3,4,9-tetrahydropyrano[ 3,4-b]-indole-1 -acetamide, then the corresponding compounds of formula I in which R is hydrogen are obtained. Examples of such compounds of formula I are listed as products in Tables VII and VIII together with the appropriate starting material, amides of formula Vll. In each case the starting material is noted by the example in which it is prepared.

TABLE VII NO. OF THE EXAMPLE IN WHICH STARTING PRODUCT, (PREFIXX LISTED BELOW)- MATERIAL 1S l,3,4,9-TETRAHYDROPYRANO[ 3,4-b1- EXAMPLE PREPARED INDOLE 310 127 1-methyl-l-[ 3-(methylamino)propyl], nmr (c001,) 81.48 (3H), 1.87 (4H), 2.47 (3H), corresponding oxalic acid addition salt has m.p. 1 10C. 31 1 128 1-(3-aminopropyl-1-methy1 312 129 1-methyl-l-[3-(dimethylamino)- propyl], m.p. 114 -116C., corresponding oxalic acid addition salt has m.pv 168 172C. 313 130 1-[ 3-(hexylamino)propyl ]-1-methyl 314 131 1-[3-(diethylamino)propyl]- l methyl 315 132 1-methyl-1-[methylamino)methyl] CHCl 316 133 1-(aminomethy1)-1-methyl, 'ymax 3465, 3400, 3180, 2930, corresponding hydrochloric acid addition salt (hydrochloride) has m.p. 251 252C. 317 134 1-[(dimethylamino)methyl]-lmethyl 318 135 1-[(hexylamino)methyl]-l-methyl 319 136 1-[(ethylamino)methyl]-1-methyl,

nmr (DMSOd 81.18 (3H), 1.62 (3H), 2.80 (2H); corresponding hydrochloric acid addition salt has m.p. 242 243C. 320 137 1-ethyl-3-methy11-[(methylamino)- methyl] 321 138 l-cyclopropyl-1-[(dimethylamino)- methyll-4-isopropyl 322 139 1 ,4-dimethyl-1[2-(dimethylamino)-ethyll 323 140 l-ethyl-l-[2-(methylamino)ethyl] 324 141 1(2-aminoethyl)-1-ethyl 325 142 1-[2-(dimethylamino)ethyl]-l-ethyl 326 143 1-ethyl-1-[2-(hexylamino)ethyl] 327 144 1-[2-(diethylamino)ethyl]-l-ethyl 328 145 l-[2-(methylamino)ethyl]-l-propyl 329 146 1-(aminoethyl)-1-propyl 330 147 l-[2-(dimethylamino)ethyl-l-propyl,

nmr(CDCl 0.84 (t,3H), 1.21 (3. 6H), 2.7) M5 5.5 cps, 2H) corresponding maleic acid addition salt has m.p. 152 154C) 331 148 1-[2-(hexylamino)ethyl]-l-propyl 332 149 1-[2-(diethylamino)ethyl]1-propyl 333 150 l-isopropyl-l-[2-(methylamino)-ethyl] 334 151 1-(2-aminoethy1) l-isopropyl 335 152 1-[2-(diethylamino)ethyl]-l-isopropyl 

1. A PROCESS FOR PREPARING A COMPOUND OF THE FORMULA 